Process for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and its trihydrated monosodium salt

ABSTRACT

The invention relates to a process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of the trihydrated monosodium salt thereof, consisting of reacting 4-aminobutyric acid with a phosphonation mixture formed by phosphorous acid and methanesulfonic anhydride and thereafter hydrolyzing the product of said reaction and isolating the products by adjustment of the pH.

This application is a 371 of PCT/ES00/00254 filed Jul. 17, 2000, now WO01/0874

FIELD OF THE INVENTION

This invention relates to an improved process for the preparation of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of thetrihydrated monosodium salt thereof, respectively known by theInternational Nonproprietary Names (INN) thereof as alendronic acid andsodium alendronate, and which are useful for the treatment andprevention of diseases involving bone resorption, such as malignhypercalcemia, Paget's disease, osteoporosis, etc.

PRIOR ART REFERENCE

U.S. Pat. No. 4,407,761 describes the preparation of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, by treating4-aminobutyric acid (GABA) with a phosphonation reactant, followed byhydrolysis of the reaction mixture by the addition of concentratedhydrochloric acid and subsequent heating of said mixture. The saidpatent describes the use of three phosphonation mixtures: H₃PO₃/PCl₃,H₃PO₃/PCl₅ and H₃PO₃/POCl₃.

U.S. Pat. No. 4,705,651 is bound to the use of a phosphonation mixtureconsisting of a mixture of H₃PO₃/PCl₃ and to a certain GABA/H₃PO₃/PCl₃stoichiometry.

It is hard to adapt these processes to industrial production, since thereaction mixture of the phosphonation step is not homogenous and tendsto solidify, preventing stirring, and also the yields obtained arevariable. Under these conditions, the subsequent hydrolysis step entailssubstantial risk, due to the presence of small drops of PCl₃ occluded inthe reaction mixture and which may cause local overheating on contactwith the hydrolyzing agent and also explosion of the gases generated.

U.S. Pat. No. 4,922,007 describes the use of methanesulfonic acid toavoid the lack of homogeneity and the solidification of the reactionmixture during the phosphonation step, to which end the ternary systemH₃PO₃/PCl₃/CH₃SO₃H is proposed. This system has been developed in otherlater patents as far as complementary aspects are concerned. Among suchpatents there may be cited EP-A-0 462 663 and U.S. Pat. No. 5,019,651,on the control of pH in the hydrolysis phase, and EP-A-0 715 631 andU.S. Pat. No. 5,648,491, concerning a continuous process.

The present inventors are unaware of other descriptions of directphosphonation of 4-aminobutyric acid proposing phosphonation reactantsother than the above mentioned mixtures.

U.S. Pat. No. 5,039,819 describes an method of indirect phosphonation of4-aminobutyric acid requiring the protection of the amino group withphthalic anhydride, activation of the acid with thionyl chloride,reaction with an alkyl phosphite and, finally, final hydrolysis of thephosphonic esters obtained, a time-consuming process which isinappropriate for industrial purposes.

There is, therefore, a need to develop alternative processes for thepreparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid andsalts thereof, allowing the industrial preparation of these products tobe simplified.

OBJECT OF THE INVENTION

The object of the present invention is a new process for the preparationof 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of thetrihydrated monosodium salt thereof, which is easily adapted toindustrial application, with good yields, which does not require the useof reactants such as PCl₃, PCl₅ or POCl₃, which are highly toxic andhazardous products for the environment, and in which the reactionmixture does not solidify.

DESCRIPTION OF THE INVENTION

The present inventors have discovered that a mixture of phosphorous acidand methanesulfonic anhydride allows the direct bisphosphonation of4-aminobutyric acid to give the corresponding4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid with good results andwithout the reaction mixture solidifying.

Consequently, the process according to the invention consists ofreacting 4-aminobutyric acid with a phosphonation mixture andhydrolyzing the resulting reaction product to subsequently isolate, byan appropriate pH adjustment, the free acid or the monosodium salt. Theessential feature of this process is that the phosphonation mixture isformed by phosphorous acid and methanesulfonic anhydride.

Although this phosphonation mixture may also be used jointly with otherauxiliary phosphonation reactants, such as PCl₃, PCl₅ or POCl₃, in aspecially preferred form the phosphonation mixture is formed exclusivelyby phosphorous acid and methanesulfonic anhydride.

In the said phosphonation mixture, the phosphorous acid/methanesulfonicanhydride molar ratio may range from 2:5 to 5:2, although a phosphorousacid/methanesulfonic anhydride molar ratio of 1:1 is preferred.

With regard to the 4-aminobutyric acid/phosphorous acid molar ratio, thelatter being the reactant providing the two phosphonic groups to thestructure of the end products, it may range from 2:1 to 5:1, 3:1 beingpreferred.

A preferred embodiment of the process according to the inventioncomprises the following steps:

(i) reacting 4-aminobutyric acid with phosphorous acid in the presenceof methanesulfonic anhydride,

(ii) hydrolyzing the reaction mixture with water,

(iii) adjusting the pH of the hydrolyzed mixture to 4.3 with theaddition of a solution of sodium hydroxide or of a basic sodium salt,

(iv) precipitating the trihydrated monosodium salt by cooling andrecovering the product obtained by filtration and drying, and if it isdesired to obtain the free acid,

(v) converting the salt obtained into the corresponding acid byneutralization thereof with an acid stronger than the4-amino-1-hydroxybutilidene-1,1-bisphosphonic acid.

The most appropriate temperatures for the bisphosphonation reactionrange from 45° C. to 125° C., preferably from 65° C. to 75° C.

Although it is not necessary, the bisphosphonation reaction ispreferably conducted in the presence of inert organic solvents which donot solubilize the reaction product. An inert solvent is understood tobe one which, in the opinion of the man or the art, does not reactsubstantially with the reactants involved. Preferred among the inertsolvents are the aromatic hydrocarbons such as xylene, toluene, benzene,etc.

Once the bisphosphonation reaction is complete, it is interrupted by theaddition of water at a temperature ranging from 0° C. to 90° C.,preferably 0° C. to 40° C. The resulting mixture is heated to atemperature above 50° C., preferably to the reflux temperature of saidmixture, to ensure complete hydrolysis. The amount of water added forthe hydrolysis is, preferably, equal to or more than 6.5 mL per gram of4-aminobutyric acid.

Preferably, prior to isolating the sodium salt by filtration, atreatment step with activated carbon is included, at a temperature belowthe boiling point of water, so as to remove remains of sulfur compounds.Alternatively, this treatment may be carried out at room temperature, oncompletion of the hydrolysis step.

If desired, once the sodium salt has been obtained, the4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid may be obtained byneutralization of a solution of the salt with an acid stronger than the4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid itself, for example,hydrochloric acid, sulfuric acid, etc., in a way clearly within thereach of a man of the art.

Another way of obtaining the4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid consists of omittingthe neutralization step on completion of the hydrolysis andprecipitating the acid directly.

The process according to the invention is simple and economic, since itonly requires simple industrial operations, the yields obtained are goodand the necessary starting raw materials may be acquired on themarketplace.

The most important advantages of the process according to the inventionconsists of: 1) avoiding the use of PCl₃, PCl₅ or POCl₃ as dehydratingagents in the phosphonation reaction, which obviates the handling ofthese reactants which are highly toxic and hazardous, as well as therelease of HCI during the reaction; and 2) the fact that the presence ofmethanesulfonic anhydride keeps the reaction mixture fluid, without theoccurrence of solidification, which makes stirring difficult.

The following examples are given for the purpose of providing the man ofthe art with a sufficiently clear and complete explanation of thepresent invention, but must not be considered as limitations on theessential aspects of the object thereof, as set forth in the foregoingparagraphs of this description.

EXAMPLES Example 1

12.53 g (0.122 mole) of γ-aminobutyric acid, 29.83 g (0.364 mole) ofphosphorous acid and 63.35 g (0.364 mole) of methanesulfonic anhydridewere charged into a 500 mL balloon flask equipped with mechanicalstirring, thermometer, cooling, nitrogen pressurization and gasadsorption traps. The thus obtained solid mixture was heated over 1 h 45min to 70° C. and was held at this temperature for 3 hours. At the endof this time, the temperature of the mixture was raised to 100° C., andwas held at this temperature for a further 3 hours. Thereafter it wasallowed to cool to room temperature and then 80.8 mL of deionized waterwere added over 15 min, with the temperature being held to between30-40° C. The thus obtained mixture was held at reflux for 6 hours(approximate temperature: 100° C.), was allowed to cool and the pH wasadjusted to 4.3 by the addition of approximately 84 mL of a 40% sodiumhydroxide solution. The suspension obtained was filtered, the solid waswashed twice over the filter with 10 mL of cold water and 49.88 g ofmoist crude product were obtained.

47.86 g of this crude product were dissolved in 24 mL of water underreflux, the solution obtained was cooled to 0-5° C. over 40 min, and washeld at this temperature for approximately 21 h 30 min, after which iswas filtered and the solid was washed twice over the filter with 5 mL ofcold water. 35.39 g of moist product were obtained, of which 32.81 gwere redissolved in 42 mL of water under reflux. The solution obtainedwas cooled to 0-5° C. over 40 min, with precipitation of the productbeing observed at 74° C. It was held at this temperature forapproximately 16 hours and was then filtered, the solid being washedtwice over the filter with 5 mL of cold water. 30.05 g of moist productwere obtained and were dried at 40° C. under vacuum until a constantweight was obtained, to give 27.24 g of sodium alendronate (trihydratedmonosodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid).Overall yield: 77.7%.

Example 2

5.92 g (0.057 mole) of γ-aminobutyric acid, 14.13 g (0.173 mole) ofphosphorous acid and 30.05 g (0.173 mole) of methanesulfonic anhydridewere charged into a 500 mL balloon flask equipped with mechanicalstirring, cooling, thermometer and nitrogen pressurization. The thusobtained mixture of solids was heated to 70° C. over 1 h 40 min and washeld at this temperature for 9 hours. At the end of this time, thereaction mixture was allowed to cool to room temperature and then 38.6mL of deionized water were added, with the temperature being held tobelow 40° C. throughout the addition. Thereafter, the mixture was heldat reflux for 6 hours (approximate temperature: 110° C.), was allowed tocool and the pH was adjusted to 4.3 by the addition of approximately 49mL of a 40% sodium hydroxide solution.

The suspension obtained was dissolved at 70° C. by the addition of 200mL of water, 0.94 g of activated carbon were charged, the mixture washeld under stirring for 30 min at 70-76° C. and was then filteredthrough a pre-layer of Avicel in hot water, the pre-layer being washedthree times with 10 mL of hot water. The 200 ml of added water wereremoved by distillation at reduced pressure and the thus obtainedsuspension was cooled to 0-5° C., was held for 3 hours at thistemperature and was then filtered, the solid being washed twice over thefilter with 10 mL of cold water. 14.06 g of moist product were obtainedand when dried at 40° C. under vacuum to a constant weight gave 12.94 gof sodium alendronate trihydrate. Overall yield: 69.3%.

Example 3

29.68 g (0.288 mole) of γ-aminobutyric acid, 70.69 g (0.862 mole) ofphosphorous acid, 150.27 g (0.862 mole) of methanesulfonic anhydride and350 mL of toluene were charged into a 500 mL balloon flask equipped withmechanical stirring, cooling, thermometer and nitrogen pressurization.The thus obtained suspension was heated to 70° C. over 1 h 40 min andwas held at this temperature for 9 h 30 min. The reaction mixture wasthen allowed to cool and 193 mL of deionized water were added over 45min, with the temperature being held to below 40° C. The mixture washeld under stirring for 30 min at room temperature and thereafter thephases were separated. The aqueous upper phase was heated and whenreflux was reached, a volume of 48 mL of water was distilled off toentrain the residual toluene. The volume of water removed bydistillation was replaced and the mixture was held under reflux for atotal of 6 hours (approximate reflux temperature: 115° C.). The thusobtained solution was adjusted to pH 4.3 by the addition of 162 mL of a40% sodium hydroxide solution.

The suspension obtained was dissolved at 70° C. by the addition of 1 Lof deionized water and 4.67 g of activated carbon were charged. Themixture was held under stirring for 30 min at 70° C., was cooled to 55°C. and was filtered at this temperature through a pre-layer of Avicel inhot water, the pre-layer being washed three times with 50 mL of hotwater. The thus obtained solution was distilled at reduced pressure toremove the volume of water (1 L) added in the previous step and the thusobtained suspension was cooled to 0-5° C. and held at this temperaturefor 3 hours. The suspension was then filtered, the solid being washedtwice over the filter with 20 mL of cold water and 73.81 g of moistcrude product were obtained.

23.01 g of this moist crude product were dissolved in 28.3 mL ofdeionized water under reflux, the thus obtained solution was cooled to0-5° C. It was filtered, with the solid being washed twice over thefilter with 5 mL of cold water and 21.21 g of moist product wereobtained which, when dried at 40° C. under vacuum to constant weight,gave 19.19 g of sodium alendronate trihydrate. Overall yield: 65.6%.

What is claimed is:
 1. A process for the preparation of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and of thetrihydrated monosodium salt thereof consisting of reacting4-aminobutyric acid with a phosphonation mixture and hydrolyzing theresulting reaction product to subsequently isolate, by an appropriate pHadjustment, the free acid or the monosodium salt, wherein thephosphonation mixture is formed by phosphorous acid and methanesulfonicanhydride.
 2. The process of claim 1, wherein the phosphonation mixtureis formed exclusively by phosphorous acid and methanesulfonic anhydride.3. The process of claim 1 or claim 2, wherein the phosphorousacid/methanesulfonic anhydride molar ratio in the phosphonation mixtureranges from 2:5 to 5:2.
 4. The process of claim 3, wherein thephosphorous acid/methanesulfonic anhydride molar ratio is 1:1.
 5. Theprocess of claim 1, wherein the phosphorous acid/4-aminobutyric acidmolar ratio ranges from 2:1 to 5:1.
 6. The process of claim 1,comprising the following steps: (i) reacting 4-aminobutyric acid withphosphorous acid in the presence of methanesulfonic anhydride, (ii)hydrolyzing the reaction mixture with water, (iii) adjusting the pH ofthe hydrolyzed mixture to 4.3 with the addition of a solution of sodiumhydroxide or of a basic sodium salt, (iv) precipitating the trihydratedmonosodium salt by cooling and recovering the product obtained byfiltration and drying, and if it is desired to obtain the free acid, (v)converting the salt obtained into the corresponding acid byneutralization thereof with an acid stronger than the4-amino-1-hydroxybutilidene-1,1-bisphosphonic acid.
 7. The process ofclaim 6, wherein step (i) is conducted at a temperature ranging from 65°C. to 75° C.
 8. The process of claim 6 or claim 7, wherein step (i) isconducted in the presence of an inert organic solvent.
 9. The process ofclaim 8, wherein the inert organic solvent is an aromatic hydrocarbon.10. The process of claim 6, wherein the phosphorous acid/methanesulfonicanhydride/4-aminobutyric acid molar ratio is 3:3:1.
 11. The process ofclaim 6, wherein in the hydrolysis of step (ii) an amount of water equalto or more than 6.5 mL is used for each gram of 4-aminobutyric acidused.
 12. The process of claim 6, wherein the solution obtained in step(ii) is heated to reflux prior to proceeding to step (iii).
 13. Theprocess of claim 6, wherein step (iii) is conducted at a temperatureranging from 15° C. to 25° C.